Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: A Pooled Cohort Analysis.

BACKGROUND: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). METHODS: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. RESULTS: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). CONCLUSIONS: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.

Natriuretic Peptides and Prognosis in Patients With Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: The prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well-known. METHODS AND RESULTS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years of follow-up for hospitalizations for HF, cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. The incidence rate per 1000 patient-years for hospitalizations for HF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4, and 40.1; P < .001) and without (1.8, 3.1, 6.0, and 19.1; P < .001) HF, with a significantly higher risk in patients with HF compared with those without (with HF, quartile 3 HR 9.28 [interquartile range (IQR) 1.15-75.05]; P = .04; without HF, quartile 4 HR 4.86 [95% CI, 2.08-11.35]; P < .001). A similar higher risk for kidney events was seen in HF patients (with HF, quartile 4 HR 6.94 [95% CI, 2.66-18.08]; P = .001; without HF, quartile 4 HR 4.85 [95% CI, 3.02-7.80]; P = .001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general, regardless of history of HF; however, the presence of a clinical diagnosis of HF at baseline was associated with an incrementally higher risk, particularly in higher NT-proBNP quartiles.

GLP-1 Receptor Agonists and Cardiovascular Disease: What Do Clinicians Need to Know?

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining importance due to their effects on cardiovascular parameters. This review discusses the findings of dedicated cardiovascular outcome trials of GLP-1RAs and summarizes their utility to help clinicians understand their role in cardiovascular disease. RECENT FINDINGS: Patients with diabetes mellitus are at an increased risk of cardiovascular disease. Cardiovascular outcome trials have shown GLP-1RAs decrease the primary composite outcome of the first occurrence of major adverse cardiovascular events (MACE) in patients with diabetes. Additionally, select GLP-1RAs have also shown improved cardiovascular outcomes in patients without diabetes who are either overweight (BMI ≥ 27), or obese (BMI ≥ 30). There have also been encouraging results in patients with heart failure with preserved ejection fraction. There is increasing evidence showing GLP-1RAs are beneficial across the cardiometabolic spectrum of disease. Implementation of these therapeutics into clinical practice is important to improve cardiovascular risk.

In adults with HF, opioids do not reduce refractory breathlessness (low-certainty evidence).

SOURCE CITATION: Gaertner J, Fusi-Schmidhauser T, Stock S, et al. Effect of opioids for breathlessness in heart failure: a systematic review and meta-analysis. Heart. 2023;109:1064-1071.36878671.

Estimated Glomerular Filtration Rate Slope as an Endpoint in Cardiovascular Trials.

PURPOSE OF REVIEW: End stage kidney disease can be a slow process and it may be challenging to achieve required follow-up for sufficient events. Therefore, a surrogate kidney endpoint, such as estimated glomerular filtration rate (eGFR) slope maybe attractive to assess the kidney in cardiovascular trials, especially heart failure (HF). RECENT FINDINGS: eGFR slope can generate informative results in a shorter follow-up period, has decreased risk of type-2 error, and is less sensitive to eGFR shifts compared with other surrogate kidney endpoints (eGFR decline≥40% or doubling creatinine). However, eGFR slope has its limitations with acute effects, heterogeneity in slope calculation/reporting, and deviations from linearity. eGFR slope is a kidney endpoint which may be well-suited for HF trials. Cross-collaborated guideline recommendations are needed to optimize the use of eGFR slope as a kidney endpoint in patients with HF.

Improving representativeness in trials: a call to action from the Global Cardiovascular Clinical Trialists Forum.

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities.

Endpoint adjudication in cardiovascular clinical trials.

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis.

BACKGROUND AND AIMS: Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. METHODS: Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. RESULTS: Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75-0.98; P = .029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75-1.01; P = .076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated. CONCLUSIONS: In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.

Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials.

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.

Comparison of 30-day Readmission Rates and Inpatient Cardiac Procedures for Weekday Versus Weekend Hospital Admissions for Heart Failure.

BACKGROUND: Whether the timing of hospital presentation impacts care delivery and clinical outcomes for patients hospitalized for heart failure (HF) remains a matter of debate. In this study, we examined all-cause and HF-specific 30-day readmission rates for patients who were admitted for HF on a weekend vs admitted for HF on a weekday. METHODS AND RESULTS: We conducted a retrospective analysis using the 2010-2019 Nationwide Readmission Database to compare 30-day readmission rates among patients who were admitted for HF on a weekday (Monday to Friday) vs patients who were admitted for HF on a weekend (Saturday or Sunday). We also compared in-hospital cardiac procedures and temporal trends in 30-day readmission by day of index hospital admission. Among 8,270,717 index HF hospitalizations, 6,302,775 were admitted on a weekday and 1,967,942 admitted on a weekend. For weekday and weekend admissions, the 30-day all-cause readmission rates were 19.8% vs 20.3%, and HF-specific readmission rates were 8.1% vs 8.4%, respectively. Weekend admissions were independently associated with higher risk of all-cause (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.03-1.05, P < .001) and HF-specific readmission (aOR 1.04, 95% CI 1.03-1.05, P < .001). Weekend HF admissions were less likely to undergo echocardiography (aOR 0.95, 95% CI 0.94-0.96, P < .001), right heart catheterization (aOR 0.80, 95% CI 0.79-0.81, P < .001), electrical cardioversion (aOR 0.90, 95% CI 0.88-0.93, P < .001), or receive temporary mechanical support devices (aOR 0.84, 95% CI 0.79-0.89, P < .001). The mean length of stay was shorter for weekend HF admissions (5.1 days vs 5.4 days, P < .001). Between 2010 and 2019, 30-day all-cause (18.5% to 18.2%, trend P < .001) and HF-specific (8.4% to 8.3%, trend P < .001) readmission rates decreased among weekday HF admissions. Among weekend HF admissions, the HF-specific 30-day readmission rate decreased (8.8% to 8.7%, trend P < .001), but the all-cause 30-day readmission rate remained stable (trend P = .280). CONCLUSIONS: Among patients hospitalized for HF, weekend admissions were independently associated with excess risk of 30-day all-cause and HF-specific readmission and a lower likelihood of undergoing in-hospital cardiovascular testing and procedures. The 30-day all-cause readmission rate has decreased modestly over time among patients admitted on weekdays, but has remained stable among patients admitted on weekends.

Managing Heart Failure in Patients on Dialysis: State-of-the-Art Review.

Heart failure (HF) and end-stage kidney disease (ESKD) frequently coexist; 1 comorbidity worsens the prognosis of the other. HF is responsible for almost half the deaths of patients on dialysis. Despite patients' with ESKD composing an extremely high-risk population, they have been largely excluded from landmark clinical trials of HF, and there is, thus, a paucity of data regarding the management of HF in patients on dialysis, and most of the available evidence is observational. Likewise, in clinical practice, guideline-directed medical therapy for HF is often down-titrated or discontinued in patients with ESKD who are undergoing dialysis; this is due to concerns about safety and tolerability. In this state-of-the-art review, we discuss the available evidence for each of the foundational HF therapies in ESKD, review current challenges and barriers to managing patients with HF on dialysis, and outline future directions to optimize the management of HF in these high-risk patients.

Inconsistent Outcome Reporting in Heart Failure Randomized Controlled Trials.

BACKGROUND: Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified. METHODS AND RESULTS: MEDLINE via PubMed was searched to include phase II-IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ2 or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (ß = -0.14; 95% CI, -0.22 - -0.01; P = 0.035). CONCLUSIONS: More than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

Minimal Clinically Important Differences in 6-Minute Walk Test in Patients With HFrEF and Iron Deficiency.

BACKGROUND: The 6-minute walk test (6MWT) is widely used to measure exercise capacity; however, the magnitude of change that is clinically meaningful for individuals is not well established in heart failure with reduced ejection fraction (HFrEF). OBJECTIVE: To calculate the minimal clinically important difference (MCID) for change in exercise capacity in the 6MWT in iron-deficient populations with HFrEF. METHODS: In this pooled secondary analysis of the FAIR-HF and CONFIRM-HF trials, mean changes in the 6MWT from baseline to weeks 12 and 24 were calculated and calibrated against the Patient Global Assessment (PGA) tool (clinical anchor) to derive MCIDs in improvement and deterioration. RESULTS: Of 760 patients included in the 2 trials, 6MWT and PGA data were available for 680 (89%) and 656 (86%) patients at weeks 12 and 24, respectively. The mean 6MWT distance at baseline was 281 ± 103 meters. There was a modest correlation between changes in 6MWT and PGA from baseline to week 12 (r = 0.31; P < 0.0001) and week 24 (r = 0.43; P < 0.0001). Respective estimates (95% confidence intervals) of MCID in 6MWT at weeks 12 and 24 were 14 meters (5;23) and 15 meters (3;27) for a "little improvement" (vs no change), 20 meters (10;30) and 24 meters (12;36) for moderate improvement vs a "little improvement,", -11 meters (-32;9.2) and -31 meters (-53;-8) for a "little deterioration" (vs no change), and -84 meters (-144;-24) and -69 meters (-118;-20) for "moderate deterioration" vs a "little deterioration". CONCLUSIONS: The MCID for improvement in exercise capacity in the 6MWT was 14 meters-15 meters in patients with HFrEF and iron deficiency. These MCIDs can aid clinical interpretation of study data.

Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial.

BACKGROUND: The presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognoses and responses to therapy in this setting. METHODS: In this post hoc analysis of the EMPEROR-Reduced trial, outcomes and the effects of empagliflozin, were assessed in study participants according to the extent (none vs mono1 vs poly [≥ 2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates are presented per 100 person-years (py) of follow-up. RESULTS: Of the 3730 study participants enrolled, 1324 (35.5%) had no vascular disease, 1879 (50.4%) had monovascular disease, and 527 (14.1%) had polyvascular disease. Participants with polyvascular disease tended to be older and male and to have had histories of hypertension, diabetes and smoking. In the placebo arm, a significantly higher risk for cardiovascular death existed in those with polyvascular disease (HR 1.57, 95% CI1.02, 2.44, compared to those with no vascular disease). In adjusted analysis, the benefit of empagliflozin in cardiovascular death or hospitalization due to HF, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores were seen across the 3 groups (interaction P > 0.05 for all) but were attenuated in those with polyvascular disease. Adverse events were higher in those with polyvascular disease, but no major differences were noted between empagliflozin or placebo assignment in the 3 groups. CONCLUSION: In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with polyvascular disease.

Kidney function assessment and endpoint ascertainment in clinical trials.

Heterogeneity in the reporting of kidney function, kidney outcomes, and definitions for kidney endpoints in clinical trials makes it challenging to compare results and gauge incremental benefit of interventions across trials. We conducted a systematic review of the ascertainment of baseline kidney variables, reporting of kidney endpoints, and definitions used to characterize these endpoints in type 2 diabetes mellitus (T2DM), kidney, and heart failure (HF) trials. Medline, Scopus, and ClinicalTrials.gov were searched from January 2014 through January 2021 for large (>1000 participants) T2DM, HF, and kidney disease trials and their secondary analyses. Trial publication and supplementary appendices were searched to abstract relevant data. Thirty-three trials (16 T2DM; 10 HF; 7 kidney diseases) were included. Thirteen trials did not include patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and for trials that did, representation of this cohort ranged from 0.1% to 15%. Reporting of baseline kidney function and albuminuria remained low, especially in HF trials. Variability was observed in the definition of chronic kidney disease, sustained decline in eGFR, end-stage kidney disease, kidney death, and kidney composite endpoint across trials. eGFR slope was reported in less than half trials, with differences observed in statistical models, definition of acute or chronic slope, and follow-up duration across trials. Significant heterogeneity in reporting of kidney function and kidney outcomes in large T2DM, kidney, and HF trials underscores the need for future stakeholders to draft a consensus solution. Detailed profiling of patients at baseline, accrual of more patients with advanced kidney disease, and standardization of definitions in trials may improve the ability to compare the results across trials.

Ni-Doped In2O3 Nanoparticles and Their Composite with rGO for Efficient Degradation of Organic Pollutants in Wastewater under Visible Light Irradiation.

The efficient degradation of organic effluent is always desirable when using advanced photocatalysts with enhanced activity under visible light. Nickel-doped indium oxide (Ni-In2O3) is synthesized via a hydrothermal route as well as its composites with reduced graphene oxide (rGO). Facile synthesis and composite formation methods lead to a well-defined morphology of fabricated nanocomposite at low temperatures. The bandgap energy of indium oxide lies in the range of 3.00-4.30 eV. Its high light absorption capacity, high stability, and non-toxicity make it a choice as a photocatalyst that is active under visible light. The transition metal Ni-doping changes the indium oxide's chemical, optical, and physicochemical properties. The Ni-In2O3 and rGO composites improved the charge transport and reduced the charge recombination. The phase analysis of the developed photocatalysts was performed using X-ray diffraction (XRD), and the morphological and structural properties were observed using advanced microscopic techniques (SEM and TEM), while UV-vis and FTIR spectroscopic techniques were used to confirm the structure and optical and chemical properties. The electrochemical properties of the photocatalysts were investigated using cyclic voltammetry (CV), linear sweep voltammetry (LSV), and electrochemical impedance spectroscopy (EIS), and the charge-transfer properties of the obtained photocatalysts and the mechanism of the photocatalytic degradation mechanism of methylene blue, a common dye used in the dyeing industry, were determined.

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Trends in hospitalizations for heart failure, acute myocardial infarction, and stroke in the United States from 2004 to 2018.

AIM: To determine the trends in hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and stroke in the United States (US). METHOD AND RESULTS: A retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004 and December 31, 2018 which included hospitalized adults ≥18 years with a primary discharge diagnosis of HF, AMI, or stroke using International Classification of Diseases-9/10 administrative codes. Main outcomes were hospitalization for HF, AMI, and stroke per 1000 United States adults, length of stay, and in-hospital mortality. There were 33.4 million hospitalizations for HF, AMI, and stroke, with most being for HF (48%). After the initial decline in HF hospitalizations (5.3 hospitalizations/1000 US adults in 2004 to 4 hospitalizations/1000 US adults in 2013, P < .001), there was a progressive increase in HF hospitalizations between 2013 and 2018 (4.0 hospitalizations/1000 US adults in 2013 to 4.9 hospitalizations/1000 US adults in 2018; P < .001). Hospitalization for AMI decreased (3.1 hospitalizations/1000 US adults in 2004 to 2.5 hospitalizations/1000 US adults in 2010, P < .001) and remained stable between 2010 and 2018. There was no significant change for hospitalization for stroke between 2004 and 2011 (2.3 hospitalizations/1000 US adults in 2004 vs 2.3 hospitalizations per 1000 US adults in 2011, P = .614); however, there was a small but significant increase in hospitalization for stroke after 2011 that reached 2.5 hospitalizations/1000 US adults in 2018. Adjusted length of stay and in-hospital mortality decreased for HF, AMI, and stroke hospitalizations. CONCLUSIONS: In contrast to the trend of AMI and stroke hospitalizations, a progressive increase in hospitalizations for HF has occurred since 2013. From 2004 to 2018, in-hospital mortality has decreased for HF, AMI, and stroke hospitalizations.

Contemporary Nationwide Heart Transplantation and Left Ventricular Assist Device Outcomes in Patients with Histories of Bariatric Surgery.

Bariatric surgery may play a role in the management of morbidly obese patients with end-stage heart failure through increasing eligibility and improving the outcomes of destination therapies. We conducted a nationally representative, retrospective cohort study of patients with previous bariatric surgery undergoing either heart transplantation or left ventricular assist device implantation. Of 200 patients, < 6% experienced in-hospital mortality after destination therapy, comparable to that reported in the general population of heart recipients. Risk-adjusted outcomes differed minimally from those of obese patients undergoing destination therapy without previous bariatric surgery. This study provides important safety benchmarking data and demonstrates the feasibility of bariatric surgery as a potential bridge to left ventricular assist device implantation or heart transplantation in obese patients with end-stage heart failure.

Subjective Financial Hardship due to Medical Bills Among Patients With Heart Failure in the United States: The 2014-2018 Medical Expenditure Panel Survey.

BACKGROUND: Heart failure (HF) poses a substantial economic burden on the United States (US) health care system. In contrast, little is known about the financial challenges faced by patients with HF. In this study, we examined the scope and sociodemographic predictors of subjective financial hardship due to medical bills incurred by patients with HF. METHODS: In the Medical Expenditure Panel Survey (MEPS; years 2014--2018), a US nationally representative database, we identified all patients who reported having HF. Any subjective financial hardship due to medical bills was assessed based on patients' reporting either themselves or their families (1) having difficulties paying medical bills in the past 12 months, (2) paying bills late or (3) being unable to pay bills at all. Logistic regression was used to evaluate independent predictors of financial hardship among patients with HF. All analyses took into consideration the survey's complex design. RESULTS: A total of 116,563 MEPS participants were included in the analysis, of whom 858 (0.7%) had diagnoses of HF, representing 1.8 million (95% CI 1.6-2.0) patients annually. Overall, 33% (95% CI 29%-38%) reported any financial hardship due to medical bills, and 13.2% were not able to pay bills at all. Age ≤ 65 years and lower educational attainment were independently associated with higher odds of subjective financial hardship due to medical bills. CONCLUSION: Subjective financial hardship is a prevalent issue for patients with HF in the US, particularly those who are younger and have lower educational attainment. There is a need for policies that reduce out-of-pocket costs for the care of HF, an enhanced identification of this phenomenon in the clinical setting, and approaches to help minimize financial toxicity in patients with HF while ensuring optimal quality of care.